Sapropterin, namely (6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H) pteridinone, of formula (I), is the synthetic version of the 6R diastereomer of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydrolase, the enzyme responsible for phenylalanine metabolism.

The structure has three stereogenic centers, two in the dihydroxypropyl side chain and the third at the connection between the side chain and the pteridine ring (C-6).
The absolute configuration (R) at this center is required to obtain the desired pharmacological effects, as the 6S diastereomer can even induce the inactivation of phenylalanine hydrolase, thus inhibiting the effects of the 6R diastereomer.
Sapropterin as the polymorph anhydrous dihydrochloride salt, Form B, is at present clinically used for the treatment of hyperphenylalaninaemia in patients suffering from phenylketonuria or BH4 deficiency.
Sapropterin, herein referred to also as 6R-Sapropterin, is prepared (Scheme 1) by platinum-mediated catalytic hydrogenation of Biopterin of formula (II) or of derivatives thereof in which the amine and/or hydroxy functionalities are protected with conventional protective groups

The hydrogenation reaction was reported for example in EP 0191335, which states that hydrogenation diastereoselectivity improves when the reaction is carried out in aqueous solution at basic pH under high hydrogen pressures.
Therefore, the synthetic problem for the preparation of Sapropterin is to obtain L-biopterin of formula (II) on an industrial scale with a safe, efficient process.
The synthesis of L-biopterin on an industrial scale is presently carried out starting from L-rhamnose of formula (III) (Scheme 2)

This synthesis involves the transformation of L-rhamnose monohydrate of formula (III), commercially available at extremely low prices, into its diethyl dithioacetal (IV) using ethanethiol both as reagent and solvent, in the presence of concentrated hydrochloric acid. Dithioacetal of formula (IV) is then oxidized with any known oxidizers to the corresponding disulfone of formula (V), which is then subjected to MacDonald-Fischer degradation under basic conditions, to provide 5-deoxy-L-arabinose of formula (VI) bearing the hydroxy functionalities of the desired absolute configuration, in aqueous solution. The reducing sugar of formula (VI) is then converted to the corresponding acetylated phenylhydrazone of formula (VII) by treatment first with phenylhydrazine and then with acetic anhydride. The compound of formula (VII) is then condensed with 6-hydroxy-2,4,5-triaminopyrimidine of formula (VIII) or a commercially available salt thereof, to give an adduct, which is not isolated but immediately subjected to oxidation to provide the acetylated biopterin of formula (IX). Basic or acid deacetylation of compound of formula (IX) yields biopterin of formula (II), which can either be isolated or maintained in solution, to be subjected to catalytic hydrogenation to provide Sapropterin of formula (I) as reported for example in above Scheme 1.
The main problem in the development of this process on an industrial scale is the preparation of 5-deoxy-L-arabinose of formula (VI), a non-natural reducing sugar, starting from L-rhamnose diethyl dithioacetal of formula (IV). 5-Deoxy-L-arabinose of formula (VI) is indeed a key intermediate in the preparation of L-biopterin of formula (II) and therefore of Sapropterin.
Ethanethiol used in this preparation is a reagent widely known for the paramount environmental problem its use involves. Ethanethiol has low boiling point (35° C.), and due to its disgusting odor that can be perceived even in a few ppm, is nowadays no longer used on an industrial scale, even in non-environmentally conscious, non-industrialized countries.
Low molecular alkylthiols, similarly to ethanethiol, are in general toxic and because of their high volatility easily contaminate the operators and the environment.
A possible solution to the problem was apparently the process disclosed in EP 1849793, which describes the preparation of L-rhamnose didodecyl dithioacetal, in yield of 75%, using dodecanethiol as the reagent. Dodecanethiol has in fact a C12 straight alkyl chain, is an inexpensive high boiling liquid, has the typical hydrocarbon odor and does not involve remarkable environmental problems, contrary to low-boiling, short chain thiols. We repeated the above described reaction, however, even when reaction parameters such as temperature, solvent, and the like were changed, it always provided (Scheme 3) mixtures of two products, namely the desired dithioacetal of formula (X) and thioglycoside of formula (XI) in nearly equimolar ratio, which are difficult to separate due to their amphiphilic nature. Therefore, the yield in the desired dithioacetal was always less than 50%. This is probably the reason why said European application has been abandoned.

Therefore, notwithstanding the efforts carried out to date to improve the synthesis of 5-deoxy-L-arabinose of formula (VI), there is still the need for an efficient, safe process for the preparation of L-biopterin of formula (II) and then Sapropterin of formula (I), or a salt thereof, on an industrial scale.